Citation (published version)

Abstract

The oncogenic MUC1-C subunit is aberrantly overexpressed in most human breast cancers by
mechanisms that are not well understood. The present studies demonstrate that stimulation of non-
malignant MCF-10A cells with epidermal growth factor (EGF) or heregulin (HRG) results in
marked upregulation of MUC1-C translation. Growth factor-induced MUC1-C translation was
found to be mediated by PI3K->AKT, and not MEK->ERK1/2, signaling. We also show that
activation of the mTORC1->S6K1 pathway decreases PDCD4, an inhibitor of the eIF4A RNA
helicase, and contributes to the induction of MUC1-C translation. In concert with these results,
treatment of growth factor-stimulated MCF-10A cells with the eIF4A RNA helicase inhibitors,
silvestrol and CR-1-31-B, blocked increases in MUC1-C abundance. The functional significance
of the increase in MUC1-C translation is supported by the demonstration that MUC1-C, in turn,
forms complexes with EGFR and promotes EGFR-mediated activation of the PI3K->AKT
pathway and the induction of growth. Compared to MCF-10A cells, constitutive overexpression of
MUC1-C in breast cancer cells was unaffected by EGF stimulation, but was blocked by inhibiting
PI3K->AKT signaling. The overexpression of MUC1-C in breast cancer cells was also inhibited
by blocking eIF4A RNA helicase activity with silvestrol and CR-1-31-B. These findings indicate
that EGF-induced MUC1-C expression is mediated by the PI3K->AKT pathway and the eIF4A
RNA helicase, and that this response promotes EGFR signaling in an autoinductive loop. The
findings also indicate that targeting the eIF4A RNA helicase is a novel approach for blocking
MUC1-C overexpression in breast cancer cells.

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